👤 Christa C Christ

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus-specific haplotype tree. Here, we develop a genome-wide LOCATER analysis pipeline and apply it to a genome sequencing study of 6795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identify 351 significant trait associations at 47 distinct genomic loci and find that LOCATER boosts the single marker test (SMT) association signal at five loci by combining independent signals from distinct alleles. LOCATER successfully recovers known quantitative trait loci not found by SMT, including Show less

A key methodological challenge for genome-wide association studies is how to leverage haplotype diversity and allelic heterogeneity to improve trait association power, especially in noncoding regions where it is difficult to predict variant impacts and define functional units for variant aggregation. Genealogy-based association methods have the potential to bridge this gap by testing combinations of common and rare haplotypes based purely on their ancestral relationships. In parallel work, we have developed an efficient local ancestry inference engine and a novel statistical method (LOCATER) for combining signals present on different branches of a locus specific haplotype tree. Here, we developed a genome-wide LOCATER analysis pipeline and applied it to a genome sequencing study of 6,795 Finnish individuals with 101 cardiometabolic traits and 18.9 million autosomal variants. We identify 351 significant trait associations at 47 distinct genomic loci and find that LOCATER boosts single marker test (SMT) association signal at 5 loci by combining independent signals from distinct alleles. LOCATER successfully recovers known quantitative trait loci not found by SMT, including Show less

Molecular imaging, which uses molecular targets due to the overexpression of specific peptide hormone receptors on the tumour surface, has become an indispensable diagnostic technique. Neuroendocrine neoplasms (NENs) especially differentiated NENs or neuroendocrine tumours (NETs) are a rare group of heterogeneous tumours, characterized by the expression of hormone receptors on the tumour cell surface. This property makes them receptive to diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides. Amongst the known hormone receptors, somatostatin receptors (SSTR) are expressed on the majority of NETs and are therefore the most relevant receptors for theranostic approaches. Current research aims to medically upregulate their expression, while other focuses are on the use of different radiopeptides (64Cu and 67Cu) or somatostatin-antagonists instead of the established somatostatin agonists. The GLP-1 receptor is another clinically relevant target, as GLP-1-R imaging has become the new standard for the localisation of insulinomas. For staging and prognostic evaluation in dedifferentiated NENs, 18F-FDG-imaging is useful, but lacks a therapeutic counterpart. Further options for patients with insufficient expression of SSTR involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4). New targets such as the glucose-dependant insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs recently and await further evaluation. For medullary thyroid cancer 18-F-DOPA imaging is standard, however this technique is rather second line for other NENs. In this area, the discovery of minigastrin, which targets the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut NENs, may improve future management. This review aims to provide an overview of the most commonly used functional imaging modalities for theranostics in NENs today and in the possible future. Show less

Neuroendocrine neoplasms (NENs) comprise a heterogeneous group of tumors, mainly localized in the gastrointestinal system. What characterizes NENs is the expression of hormone receptors on the tumor cell surface, making them accessible for diagnostic and therapeutic approaches (theranostics) using radiolabelled peptides. Somatostatin receptors subtype-two (SST2) play an important role in NENs since they are overexpressed and homogeneously distributed at the surface of the majority of NENs. Accordingly, targeting SST2 for diagnostic and therapeutic purposes has been established. Current research aims at upregulating its expression by epigenetic treatment or improving its targeting via use of alternative radioligands. In addition, recent data suggest a future role of SST antagonists as a diagnostic tool and a potential therapeutic option. Another promising target is the glucagon-like peptide-1 (GLP-1) receptor. Targeting GLP-1R using exendin-4 (GLP-1 analogue) has a high sensitivity for the localization of the often SST2-negative sporadic insulinomas and insulinomas in the context of multiple endocrine neoplasia type-1. Further options for patients with insufficient expression of SST2 involve metaiodobenzylguanidine (MIBG) and the molecular target C-X-C motif chemokine receptor-4 (CXCR4), which have been evaluated for potential theranostic approach in symptomatic NENs or dedifferentiated tumors. Recently, new targets such as the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the fibroblast activation protein (FAP) have been identified in NENs. Finally, minigastrin - a ligand targeting the cholecystokinin-2 (CCK2) receptors in medullary thyroid carcinoma and foregut neuroendocrine tumors - may improve future management of these diseases with currently limited therapeutic options. This review summarises the current approaches and future challenges of diagnostic and therapeutic evaluations in neuroendocrine neoplasms. Show less

Hypertrophic cardiomyopathy (HCM) patients are at increased risk of ventricular arrhythmias and sudden cardiac death, which can occur even in the absence of structural changes of the heart. HCM mouse models suggest mutations in myofilament components to affect Ca Show less

Hypertrophic cardiomyopathy (HCM) is often accompanied by increased myofilament Ca(2+) sensitivity and diastolic dysfunction. Recent findings indicate increased late Na(+) current density in human HCM cardiomyocytes. Since ranolazine has the potential to decrease myofilament Ca(2+) sensitivity and late Na(+) current, we investigated its effects in an Mybpc3-targeted knock-in (KI) mouse model of HCM. Unloaded sarcomere shortening and Ca(2+) transients were measured in KI and wild-type (WT) cardiomyocytes. Measurements were performed at baseline (1 Hz) and under increased workload (30 nM isoprenaline (ISO), 5 Hz) in the absence or presence of 10 µM ranolazine. KI myocytes showed shorter diastolic sarcomere length at baseline, stronger inotropic response to ISO, and drastic drop of diastolic sarcomere length under increased workload. Ranolazine attenuated ISO responses in WT and KI cells and prevented workload-induced diastolic failure in KI. Late Na(+) current density was diminished and insensitive to ranolazine in KI cardiomyocytes. Ca(2+) sensitivity of skinned KI trabeculae was slightly decreased by ranolazine. Phosphorylation analysis of cAMP-dependent protein kinase A-target proteins and ISO concentration-response measurements on muscle strips indicated antagonism at β-adrenoceptors with 10 µM ranolazine shifting the ISO response by 0.6 log units. Six-month treatment with ranolazine (plasma level >20 µM) demonstrated a β-blocking effect, but did not reverse cardiac hypertrophy or dysfunction in KI mice. Ranolazine improved tolerance to high workload in mouse HCM cardiomyocytes, not by blocking late Na(+) current, but by antagonizing β-adrenergic stimulation and slightly desensitizing myofilaments to Ca(2+). This effect did not translate in therapeutic efficacy in vivo. Show less

Some of the genetic vulnerability for addiction may be mediated by impulsivity. This study investigated relationships among impulsivity, substance use problems and six neurexin-3 (NRXN3) polymorphisms. Neurexins (NRXNs) are presynaptic transmembrane proteins that play a role in the development and function of synapses. Impulsivity was assessed with the Barratt Impulsiveness Scale Version 11 (BIS-11), the Boredom Proneness Scale (BPS) and the TIME paradigm; alcohol problems with the Michigan Alcoholism Screening Test (MAST); drug problems with the Drug Abuse Screening Test (DAST-20); and regular tobacco use with a single question. Participants (n=439 Caucasians, 64.7% female) donated buccal cells for genotyping. Six NRXN3 polymorphisms were genotyped: rs983795, rs11624704, rs917906, rs1004212, rs10146997 and rs8019381. A dual luciferase assay was conducted to determine whether allelic variation at rs917906 regulated gene expression. In general, impulsivity was significantly higher in those who regularly used tobacco and/or had alcohol or drug problems. In men, there were modest associations between rs11624704 and attentional impulsivity (p=0.005) and between rs1004212 and alcohol problems (p=0.009). In women, there were weak associations between rs10146997 and TIME estimation (p=0.03); and between rs1004212 and drug problems (p=0.03). The dual luciferase assay indicated that C and T alleles of rs917906 did not differentially regulate gene expression in vitro. Associations between impulsivity, substance use problems and polymorphisms in NRXN3 may be gender specific. Impulsivity is associated with substance use problems and may provide a useful intermediate phenotype for addiction. Show less

Nogo-A is one of the most potent oligodendrocyte-derived inhibitors for axonal regrowth in the injured adult CNS. However, the physiological function of Nogo-A in development and in healthy oligodendrocytes is still unknown. In the present study, we investigated the role of Nogo-A for myelin formation in the developing optic nerve. By quantitative real-time PCR, we found that the expression of Nogo-A increased faster in differentiating oligodendrocytes than that of the major myelin proteins MBP (myelin basic protein), PLP (proteolipid protein)/DM20, and CNP (2',3'-cyclic nucleotide 3'-phosphodiesterase). The analysis of optic nerves and cerebella of mice deficient for Nogo-A (Nogo-A(-/-)) revealed a marked delay of oligodendrocyte differentiation, myelin sheath formation, and axonal caliber growth within the first postnatal month. The combined deletion of Nogo-A and MAG caused a more severe transient hypomyelination. In contrast to MAG(-/-) mice, Nogo-A(-/-) mutants did not present abnormalities in the structure of myelin sheaths and Ranvier nodes. The common binding protein for Nogo-A and MAG, NgR1, was exclusively upregulated in MAG(-/-) animals, whereas the level of Lingo-1, a coreceptor, remained unchanged. Together, our results demonstrate that Nogo-A and MAG are differently involved in oligodendrocyte maturation in vivo, and suggest that Nogo-A may influence also remyelination in pathological conditions such as multiple sclerosis. Show less